Project Summary/ Abstract The hippocampus and prefrontal cortex (PFC) are both critical for learning and memory-guided behavior, with the hippocampus necessary for rapid episodic learning and memory, and PFC playing an integral role in long- term memory, retrieval, working memory and decision making. Coordination of neural activity between these regions is necessary for these cognitive processes, however, it is still unclear what features of neural activity mediate interactions for communication of memory-related information, and the explicit roles of these activity patterns in learning, retrieval and decision making. This proposal will investigate the roles of prominent physiological network patterns by combining behavioral methods in rats, high-density recording, and a novel closed-loop optogenetic perturbation technique that can detect network patterns in real-time and disrupt inter- regional coordination. First, we will simultaneously and continuously monitor activity of neural populations in the hippocampus and PFC over the course of learning of a novel spatial memory task. Previous work suggests that two prominent patterns can mediate hippocampal-prefrontal interactions; coherence during theta oscillations associated with place cell activity, and coordinated reactivation of behavioral experiences during awake sharp-wave ripples (SWRs). We will test if awake SWR reactivation during initial exploration supports memory formation by establishing associations between hippocampal-prefrontal neurons, and if theta coherence mediates retrieval of these associations during later exploitation to support ongoing decision making. Next we will use real-time detection and closed-loop optogenetic perturbation to disrupt coordination during specific physiological patterns. We will test if disrupting coordinated reactivation using optogenetic perturbation of prefrontal reactivation during awake hippocampal SWRs impairs memory formation and behavioral learning. Further, we will test if disrupting phase-locked prefrontal spiking during theta coherence impairs retrieval and memory-guided decision making. Finally, we will investigate if reactivation during sleep and awake SWRs play different roles in learning. We will examine differences in prefrontal reactivation for awake vs. sleep SWRs, and test the causal role of sleep SWRs in consolidation by disrupting prefrontal reactivation during sleep. Together, these aims will provide an integrated, causal understanding of the role of prominent network activity patterns in hippocampal-prefrontal interactions necessary for learning and memory- guided behavior. This proposal will thus provide crucial insight into memory disorders associated with these regions such as dementia, PTSD, Alzhiemer's disease, and also neuropsychiatric disorders such as autism and schizophrenia.